BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis.
Journal:
Mol. Cell 2001 SepAuthors:
Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T, Korsmeyer SJ
Abstract
Critical issues in apoptosis include the importance of caspases versus organelle dysfunction, dominance of anti- versus proapoptotic BCL-2 members, and whether commitment occurs upstream or downstream of mitochondria. Here, we show cells deficient for the downstream effectors Apaf-1, Caspase-9, or Caspase-3 display only transient protection from "BH3 domain-only" molecules and die a caspase-independent death by mitochondrial dysfunction. Cells with an upstream defect, lacking "multidomain" BAX,
...[more]BAK demonstrate long-term resistance to all BH3 domain-only members, including BAD, BIM, and NOXA. Comparison of wild-type versus mutant BCL-2, BCL-X(L) indicates these antiapoptotics sequester BH3 domain-only molecules in stable mitochondrial complexes, preventing the activation of BAX, BAK. Thus, in mammals, BH3 domain-only molecules activate multidomain proapoptotic members to trigger a mitochondrial pathway, which both releases cytochrome c to activate caspases and initiates caspase-independent mitochondrial dysfunction.[less]
Mesh Headings:
Animals, Apoptosis, Apoptosis Regulatory Proteins, Apoptotic Protease-Activating Factor 1, BH3 Interacting Domain Death Agonist Protein, Carrier Proteins, Caspases, Cell Line, Cytochrome c Group, Enzyme Precursors, Immunoblotting, Membrane Proteins, Mitochondria, Protein Structure, Tertiary, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Recombinant Proteins, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein, bcl-Associated Death Protein, bcl-X Protein